Neurodegenerative disorders (NDs) and diseases often have in common a neurodegenerative component that leads both to movement disorders, such as ballism, ataxia, hyperkinesis, Parkinsonims, athetosis, chorea, dyskinesias, and the like, as well as neuropsychiatric symptoms. In particular, Huntington's Disease (HD), Parkinson's Disease (PD), Alzheimer's Disease (AD) each present a constellation of symptoms. For example, HD, PD, and/or AD each may present symptoms including movement disorders or dysfunctions, as well as neuropsychiatric disorders, such as aggression, irritability, and anger. Though certain movement disorders, such as chorea, may be treated with drugs approved for certain neurodegenerative diseases, such as HD and PD, the neuropsychiatric aspects of neurodegenerative diseases are left untreated because traditional medications have not proved to be effective. Left untreated, such neuropsychiatric symptoms may lead to a wide range of complex, comorbid, and often unrelated downstream consequences. Accordingly, there is a current need for compounds, compositions, and methods for treating the neuropsychiatric aspects of neurodegenerative disorders and diseases.
HD is an inherited disease that results from expansion of a trinucleotide (CAG, cytosine/adenine/guanine) repeat that encodes a polyglutamine tract in the huntingtin protein. Onset is typically between 35 and 44 years of age, but it may begin much earlier or later. Symptoms include declines in behavioral, cognitive, and motor function. Psychiatric symptoms, including irritability and aggression, are common in HD patients and are among the most distressing aspects of the disease. For 40% to 70% of HD patients, irritability and aggression adversely affect daily life and often result in institutionalization (van Duijn et al., Psychopathology in verified Huntington's disease gene carriers. J Neuropsychiatry Clin Neurosci. 19:441-8 (2007)). Despite the frequent occurrence and severe consequences of irritability and aggressive behavior in HD, these symptoms have received little attention. Various assessment tools have been used to measure irritability in HD, including the Neuropsychiatric Inventory (NPI), the Unified Huntington Disease Rating Scale, the Irritability Scale (Chatterjee), and the Problem Behaviors Assessment for Huntington's Disease (PBA-HD). Nonetheless, blinded treatment studies in HD or long term follow-up studies of drug therapies for the neuropsychiatric aspects of HD, such as irritability and aggression, have not been conducted.
It has also been reported that currently available medications that have been observed to be effective in treating aggression, irritability, and anger, and/or depression and anxiety in other diseases, such as major depressive disorder and generalized anxiety disorder, either fail or are only transiently effective in treating the neuropsychiatric symptoms of HD, PD, and/or AD. For example, it has been reported that treatment with the antidepressant venlaxafine XR in HD patients improved depressive symptoms but led to increased irritability. Similarly, in AD patients, treatment with the antipsychotic risperidone only transiently reduced aggression, and was ineffective after 12 weeks. Similarly, aripiprazole also only provided transient effects. Moreover, recent government guidance has cautioned against using antipsychotics in elderly patients to treat dementia due to the observation of serious side effects and the general health risks associated with those drugs, including extrapyramidal symptoms, accelerated cognitive decline, stroke, and death. Therefore, those drugs are not considered a good choice for clinical use in treating neurodegenerative diseases, and it is specifically recommended that they are only used for short-term treatment (see, Ballard & Corbett, CNS Drugs 24(9):729-739 (2010)).
Those treatment failures also suggest that the nature of the neuropsychiatric symptoms are distinct HD, AD, and PD. Stated another way, irritability, anger, aggression, depression, and anxiety in HD, AD, and PD are not the same as those apparently same behavioral endpoints in other diseases, such as paranoid schizophrenia, epilepsy, major depressive disorder, and the like, that can be treated effectively with drugs that are currently available. Without being bound by theory, it is believed herein that the outward manifestations of the neuropsychiatric aspects associated with HD, PD, and/or AD, such as aggression, irritability, and anger have a distinct underlying cause. Therefore, aggression, irritability, and anger, and depression and anxiety arising in patients suffering from HD, PD, and/or AD, is a separate disorder or dysfunction, and unrelated to aggression, irritability, and anger in other diseases. Further support for that conclusion arises from reports that, for example, irritability may be seen in a number of diseases and disorders, yet the underlying cause or dysfunction that manifests as irritability can be different in each case. Examples of such disorders include MOA-A deficiency, traumatic brain injury, stroke, mental retardation, major depressive disorder, bipolar disorder, and the like, each of which manifest in irritability or aggressive behavior. In particular, it has been reported that excessive signaling through vasopressin V1b receptors is responsible for various neuropsychiatric symptoms, inducing stress-related disorders, anxiety, depression, memory dysfunction, aggression, and social behavior (see, Ślusarz, “Vasopressin V1a and V1b receptor modulators: a patent review (2012-2014)” Expert Opinion Ther. Patents (2015)). Therefore, without being bound by theory, it is also believed herein that the reported treatment failures may arise from targeting the incorrect underlying causes of the neuropsychiatric symptoms specific to HD, AD, and/or PD. The treatment of the neuropsychiatric symptoms of HD/AD/PD, such as aggression, irritability, anger, depression, and anxiety is an unmet medical need.
It has been surprisingly discovered herein that altering vasopressin signaling in the central nervous system (CNS) is efficacious in treating the neuropsychiatric aspects, sometimes termed Behavioral and Psychological Symptoms in Dementia (BPSD), in neurodegenerative disorders and diseases, including, but not limited to HD, AD, and/or PD. In particular, it has surprisingly been discovered herein that neurodegenerative disorders and diseases, including but not limited HD, PD, and AD, and in particular the neuropsychiatric aspects thereof, may be treated by administering vasopressin antagonists that achieve therapeutically effective concentrations in the CNS. It has also been surprisingly discovered herein that compounds and compositions described herein show CNS effects after oral administration, and modulate specific brain circuits involved in responses to stimuli that result in irritability and aggression, and other neuropsychiatric aspects of ND in HD, AD, and PD patients.
Interestingly, there is no evidence that elevated arginine vasopressin (AVP) levels are present in the CNS of patients with HD, PD, and/or AD. In addition, elevated arginine vasopressin receptor (AVPR) expression levels in the CNS are not observed in patients with HD, PD, and/or AD. Given that neurodegeneration is one of the hallmarks of HD, PD, and AD, a pathology that includes the destruction of, or compromising of tissues in the brain that control executive functions might be expected. For example, the neuropsychiatric symptoms specific to HD, PD, and AD may arise from destruction of the brain tissues that are responsible for controlling executive functions. However, the opposite has been discovered herein regarding AVPR expression levels, which are otherwise similar to expression levels in those not suffering from HD, PD, or AD. Therefore, from a pathophysiological perspective, host animals suffering from HD, PD, and/or AD cannot be distinguished from normal cohorts on that basis. Nonetheless, though without being bound by theory, it is believed herein that the neuropsychiatric aspects of neurodegenerative disorders and diseases such as HD, PD, and/or AD may result from a condition-dependent excessive vasopressin signaling or an increase in vasopressin signaling, though not due to elevated AVP levels or overexpression of AVPR compared to non-diseased individuals. Instead, it is believed herein that the neuropsychiatric aspects of diseases such as HD, PD, and/or AD are due to condition-dependent AVP hypersensitivity in the CNS. Accordingly, apparently otherwise normal AVP levels nonetheless cause excessive vasopressin signaling in host animals with HD, PD, and/or AD. Without being bound by theory, it is also believed herein that the efficacy of the compounds, compositions, and methods described herein is due at least in part to modulating, correcting, or even preventing excessive vasopressin signaling even in the absence of excessive AVP concentrations or AVP expression in the CNS. In addition, though without being bound by theory, it is believed herein that the excessive vasopressin signaling that arises from AVP hypersensitivity leads to a dysfunction of or a loss of executive control function. That dysfunction or loss of function leads to a loss in the ability to appropriately control situationally dependent inappropriate behavior, such as aggression, irritability, and anger, and/or to make situationally dependent appropriate decisions, especially under stress or anxiety.
These surprising discoveries and the invention described herein are related to the treatment of what might otherwise be considered normal vasopressin signaling, where in the diseased host animal other inhibitory or corrective systems are ineffective or cannot accommodate the condition-dependent excessive vasopressin signaling. Thus, administration of the compounds or compositions described herein decreases vasopressin signaling to a level lower than would otherwise be considered as normal, bringing the dysregulated signaling systems, including those that control executive functions, back into balance.
In one illustrative embodiment of the invention, selective V1a vasopressin antagonists, and compositions and methods for using such vasopressin antagonists, are described herein. In another illustrative embodiment, selective V1a vasopressin antagonists, and compositions and methods for using such vasopressin antagonists, that are configured to achieve or capable of generating CNS concentrations of at least about 100 nM upon administration to a host animal are described herein. In another illustrative embodiment, selective V1a vasopressin antagonists, and compositions and methods for using such vasopressin antagonists, that are configured to achieve or capable of generating CNS concentrations of at least about 10 nM, or at least about 1 nM upon administration to a host animal are described herein. In another illustrative embodiment, selective V1a vasopressin antagonists, and compositions and methods for using such vasopressin antagonists, that are configured to achieve or capable of generating CNS concentrations of at least about 100 pM, at least about 10 pM, or at least about 1 pM, upon administration to a host animal are described herein.
It is appreciated herein that the neuropsychiatric aspects of neurodegenerative diseases such as HD, PD, and/or AD may present in advance of chorea, or other movement disorders. Accordingly, if diagnosed early in disease progression, the compounds, compositions, and methods described herein may also be effective in delaying the onset of movement disorders and other later stage symptoms or aspects of neurodegenerative diseases. Also described herein are compounds, compositions, and methods for the prophylactic treatment of neurodegenerative diseases such as HD, PD, and/or AD, such as the prophylactic treatment of movement disorders and dysfunctions and other later stage symptoms.
It has been discovered herein that neurodegenerative disorders and diseases such as HD, PD, and AD, and in particular the neuropsychiatric aspects thereof, are treatable with selective vasopressin V1a antagonists. In one embodiment, the vasopressin receptor antagonists are of the formula
and pharmaceutically acceptable salts thereof; wherein
A is a carboxylic acid, an ester, or an amide;
B is a carboxylic acid, an ester, or an amide; or B is an alcohol or thiol, or a derivative thereof;
R1 is hydrogen or C1-C6 alkyl;
R2 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halo, haloalkyl, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of —CO2R8, —CONR8R8′, and —NR8(COR9); where R8 and R8′ are each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl; or R8 and R8′ are taken together with the attached nitrogen atom to form a heterocyclyl group; and where R9 is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R8R8′N—(C1-C4 alkyl);
R3 is an amino, amido, acylamido, or ureido group, which is optionally substituted; or R3 is a nitrogen-containing heterocyclyl group attached at a nitrogen atom; and
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylhaloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted arylhaloalkenyl, or optionally substituted arylalkynyl.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a host animal with a neurodegenerative disease. It is to be understood that the compositions may include other components and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like, and combinations thereof. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating host animals with a neurodegenerative disease are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to the host animal. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating host animals a neurodegenerative disease. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating host animals with a neurodegenerative disease are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions described herein.
It is to be understood herein that the compounds described herein may be used alone or in combination with other compounds useful for treating neurodegenerative diseases, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is to be understood herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of a neurodegenerative disease, such as compounds administered to treat chorea or other movement disorders, and the like.